Tumor markers

Tumor markers in Oncology.

1. TUMOUR MARKERS IN ONCOLOGY

2. What are tumor markers? Tumor markers are substances that are produced by cancer or by other cells of the body in response to cancer or certain benign (noncancerous) conditions. Most tumor markers are made by normal cells as well as by cancer cells; however, they are produced at much higher levels in cancerous conditions. These substances can be found in the blood, urine, stool, tumor tissue, or other tissues or bodily fluids of some patients with cancer. Most tumor markers are proteins. Patterns of gene expression and changes to DNA have also begun to be used as tumor markers.

3. the Ideal Tumor Marker High sensitivity and very high disease specificity Specific production by premalignant or malignant tissue early in the progression of disease Produced at detectable levels in all patients with a specific malignancy Expression in an organ site-specific manner Evidence of presence in bodily fluids obtained noninvasively or in easily accessible tissue Levels related quantitatively to tumor volume Relatively short half-life , reflecting temporal changes in tumor burden and response to therapy Existence of a standardized, reproducible assay that is widely available at a reasonable cost .

4. Classifiction of tumor markers

5. Tumor markers Tumor derived markers Tumor associated markers Originate from neoplastic cells Originate from cells other than malignancy in response to tumors Eg. steroids from adrenocortical tumors Eg. Liver produce acute phase protein in response to tumors Can arise from tumor stroma Eg. Hypercalcemia factors from breast cancers Produced by tissue infiltration by metastasis Eg. Hydroxyprolin in urine in c/o osteolytic bone metastasis

6. Clinical application of tumor markers Screening and Early detection of cancer – PSA for prostate cancer ; AFP for HCC in endemic area Diagnosis – CA 125 strongly associated with ovarian cancer Gastrin (gastrinoma), Insulin (insulinoma) Calcitonin – MTC S. AFP > 500ng/ml with cirrhosis – HCC Brain tumors where biopsy not feasible. Staging – AFP, beta-HCG, LDH for testicular cancers Determining the prognosis CEA – colorectal cancer Her2, ki 67 – breast cancer AFP, LDH , B-HCG– testicular cancer

7. Clinical application of tumor markers Determining effectiveness of treatment – CEA, Thyroglobulin, CA-125, PSA Detection of recurrence on follow up CA-125 for epithelial ovarian cancer (3 months earlier) PSA – prostate cancer HCG – GTT, germ cell tumors of ovaries and testis CEA – colorectal cancer CA 15-3 – breast cancer Thyroglobulin – papillary/ Follicular ca

8. Recommendation for ordering tumor markers Do serial testing Same lab While monitoring for recurrence make sure that the level was elevated before surgery Consider half life while interpreting the result Know the metabolism of tumor marker Do panel testing than single marker

9. AFP ,  αlpha-fetoprotein AFP is a major plasma glycoprotein produced by the yolk sac and the fetal liver-kupffer cells during fetal development It is thought to be the fetal analog of serum albumin.  Normal serum value : <15 ng/ml T ½ : 4 to 6 days Elevated in High levels (>500ng/ml) – in HCC & NSGCT Markedly incresed levels (>1000ng/ml) tumor size 3cm

10. Tumors associated with elevated AFP Hepatocellular carcinoma – 80% cases Metastatic disease affecting the liver Nonseminomatous germ cell tumors of testis - Yolk sac tumor/ embryonal / mixed GCT Ovarian germ cell tumors (20%) except dysgerminoma CSF:plasma ratio of AFP > 1:40 – CNS involvement False positive 🡪 in benign conditions causing liver parenchymal inflammation and necrosis Hepatitis Pregnancy Primary biliary cirrhosis Extrahepatic biliary obstruction

11. Developmental birth defects a/w elevated AFP Omphalocele ,Gastroschisis Neural tube defects: ↑ α-fetoprotein in amniotic fluid and maternal serum Ataxia : elevated AFP is used as one factor in diagnosis Decreased in downs syndrome

12. For screening – can be combined with USG for early cases of HCC in high risk areas For follow up – normalization of levels within 25-30 days is indicative of appropriate decline For staging of testicular cancers along with beta- HCG and LDH

13. Carcinoembryonic antigen  ( CEA ) glycoproteins involved in cell adhesion Normally produced in GIT of fetal development and then again raised in some cancers Normal value : <2.5ng/ml in non-smokers <5ng/ml in smokers T ½ - 1-7 days

14. CEA levels elevated in  Malignancy Colorectal carcinoma gastric carcinoma,  pancreatic carcinoma,  lung carcinoma,  breast carcinoma, and  medullary thyroid carcinoma Benign ulcerativecolitis,  pancreatitis,  cirrhosis, COPD,  Crohn's disease, hypothyroidism in smokers.

15. Cea Level is incresed with Well-differentiated tumors Lymph node and distant metastasis Left-sided tumors Tumors causing bowel obstruction Aneuploid tumors Liver dysfunction

16. Uses of cea Prognosis : preoperative CEA>5ng/ml 🡪 decrease OS As a measure of completeness of tumor resection Monitoring tumor recurrence after surgery within 3-4 months even CT is normal Monitor tumor regression in metastatic disease

17. psa – prostate specific antigen Glycoprotein secreted by prostate acinar and ductal cells PSA is produced for the ejaculate, where it liquefies semen in the seminal coagulum and allows sperm to swim freely Normal value : 2.5-4ng/ml T ½ : 2-3 days Levels <4ng/ml – less likely cancer 4-10 ng/ml – benign disease (BPH, prostatitis) vs prostate cancer >10ng/ml - likely to be cancer Transient increase in PSA may be after ejaculation, catheterization, vigorous bicycle exercise

18. Free Psa vs bound psa Most PSA in the blood is bound to serum proteins free to total ratio < 25% - increase cancer risk promising for eliminating unnecessary biopsies in men with PSA levels between 4 and 10 ng/mL.

19. uses For screening of prostate cancer The role is controversial : benefit of early diagnosis vs risk of overdiagnosis and over treatment High sensitive but less specific US FDA has approved the PSA test for annual screening of prostate cancer in men of age 50 and older along with DRE UK national health service allows patients to decide with discussion with doctor Risk stratification and staging Low-risk: PSA < 10, Gleason score ≤ 6, AND clinical stage ≤ T2a Intermediate-risk: PSA 10-20, Gleason score 7, OR clinical stage T2b/c High-risk: PSA > 20, Gleason score ≥ 8, OR clinical stage ≥ T3

20. Post-treatment monitoring Post radical prostatectomy – PSA becomes undetectable Failure of radiation to decrease PSA <1ng/ml – s/o recurrence Biochemical recurrence – when PSA level increases on 3 consecutive testing PSA doubling time – time required for increase in PSA twofold After radical prostatectomy doubling time reflects aggressiveness of original cancer PSA velocity Normal – 0.04ng/ml/yr for age 60 yrs If rapid rate of increase (>0.75ng/ml/yr or >20%) correlates with cancer

21. Psma – prostate specific mambrane antigen Newer biomarker for prostate cancer Higher values associated with early progression and relapse Current use is limited to PSMA scan – look for metastasis Can be a target for treatment Lutetium bound to PSMA to treat the prostate cancer

22. Ca - 125 Glycoprotein normally expressed in coelomic epithelium during fetal development Normal value : <35U/ml T ½ : 4-5 days Elevated in Malignancy >90% cases of advanced epithelial ovarian cancer cervical endocarcinoma, Endometrial adenocarcinoma, trophoblastic tumors of liver , lung Non hodgkins lymphoma representing pleuropericardial or peritoneal involvement Benign : cirrhosis, Renal failure, menstruation, endometriosis, pregnancy

23. uses To aid in diagnosis High levels a/w non mucinous ovarian cancer in >90% Normal level does not exclude tumor Can not distinguish benign and malignant pelvic mass Values >65U/ml correlate with peritoneal involvement To know response to treatment and follow up Correlates with poorer prognosis if elevated 3-6 weeks after surgery Level >35U/ml – residual tumor Rising level during chemotherapy – tumor progression – precede clinical recurrence by many months

24. For prognosis Preoperative value >65 U/ml 🡪 poor prognosis Post surgery – 50% decline within 5 days 🡪 good prognosis Normalization within 3 cycles of chemotherapy 🡪 good prognosis

25. CA 19 - 9 Blood group carbohydrate 🡪 sialylated derivative of Lewis antigen Synthesized by normal human pancreatic and biliary ductal cells Normal value : <37U/ml elevated in Malignancy : Pancreatic cancer (70-90%) Colorectal cancer (20-40%) Biliary tract cancer Benign : pancreatitis, primary biliary tract disease , cirrhosis

26. C 19 - 9 Very high levels (>1000 U/ml) are often associated with surgically unresectable lesions Mainly used for following the pancreatic cancer patients. Post surgical increase concentration correlates with recurrence

27. Beta- HCG Placental polypeptide hormone produced by syncytiotrophoblast Normal value : <5mIU/ml for women <3mIU/ml for men T ½ :18-24 hours Elevated in Malignant GTN (Gestational trophoblastic neoplasia) mainly choriocrcinoma Germ cell tumors of testis and ovary Benign During pregnancy / ectopic pregnancy

28. Beta HCG used for initial diagnosis, determine prognosis, follow up response to treatment and detect recurrence early. Beta HCG does not cross bloodbrain barrier .. CSF: serum ratio >1:60, if ratio is less than this 🡪cerebral metastsis

29. Ca 15-3 Glycoprotein antigen Normal value : <25U/ml T ½ : <2 weeks Elevated in Malignancy : breast cancer, pancrease, gastric, ovarian, lung, liver cancer Benign: chronic hepatitis, cirrhosis, sarcoidosis, TB Used to monitor response to treatment, to detect recurrence early in all stages of breast cancers

30. calcitonin Hormone produced by parafollicular C cells of thyroid gland It helps to regulate blood calcium levels Normal value : 0.2-25 pg/ml T ½ : 12 min Eleveted in Malignancy: medullary thyroid carcinoma lung cancer Benign : thyroid nodules Used for diagnosis of MTC – basal calcitonin <25 pg/ml or calcium stimulated <100 pg/ml

31. Chromogranin A and neuron specific enolase (nse) Normal value : <76ng/ml in men <51ng/ml in women Elevated in NET(neuroendocrine tumors) Carcinoid tumors Neuroblastoma Small cell lung cancer Pancreatic islet cell tumor

32. conclusion Tumor markers have changed the diagnosis and management of patients with malignancy Important role in screening of prostate cancer, staging testicular cancer, prognosis in colorectal cancer Evaluated for screening of HCC, epithelial ovarian neoplasia Newer genetic markers are introduced

33. Thank you….